The goal of this Program Project application is to further the understanding of the human neurobiology of nicotine by examining brain mechanisms and behaviors that define nicotine dependence. it consists of 4 closely coordinated research projects adopting 3 approaches to further these aims: Imaging--to specify nicotine's locus of action in the normal human brain using PET; Psychopharmacology--to examine how cognitive deficits associated with psychiatric cofactors can reinforce (and overdetermine) smoking; and Behavioral genetics -- to increase knowledge about the heritability of nicotine's reinforcing effects via behavioral genetics research on individual differences in nicotine sensitivity and metabolism. Research Projects will test these hypotheses: Project 1: Acute nicotine doses will cause reliable regional changes in cerebral bloodflow and metabolism; Project 2: Where nicotine withdrawal effects overlap with ADHD symptomatology, affected individuals will experience severe and persistent nicotine abstinence symptomatology, which will be reduced by methylphenidate administration; neither diagnostic nor medication status will affect nicotine sensitivity; Project 3: Genetic influences on nicotine use can be partitioned into influences associated with cofactors (depression, childhood conduct disorder, ADHD) and influences associated with nicotine sensitivity; Project 4: Individual differences in nicotine disposition and kinetics are heritable; metabolic differences can be differentiated from environmental factors associated with smoking. Support will be provided by 3 Cores: The Administrative Core will facilitate communication, integration, and shared mission as well as ensure quality control; oversight will be provided by an External Advisory Board, which will meet annually to review progress and policy, and an Internal Advisory board, which will meet quarterly to advise on progress and use of resources. The Assessment Services Core will provide standardized assessment of nicotine dependence and cofactors across projects. The Assay Services Core will conduct nicotine/cotinine and other assays needed by the Research Projects. Health Significance: Cigarette smoking is associated with over 400,000 premature deaths per year in the U.S. Over the past decade, there has been substantial progress in defining mechanisms for nicotine reinforcement at the molecular and animal level; understanding aat the human level, however, has lagged behind. The long-term objective is to help redress this deficiency. A larger implication is that the widespread use of nicotine and its potent pharmacology make it an excellent model of drug abuse in general.